Iontophoresis drug delivery system and method for denervation of the renal sympathetic nerve and iontophoretic drug delivery

ABSTRACT

An iontophoresis drug delivery system and method for denervation of the renal sympathetic nerve and iontophoresis drug delivery. The system includes an iontophoresis catheter fitted with a drug coated balloon. The iontophoresis catheter includes a balloon near its distal tip or end that contacts the vessel wall circumferentially when inflated. One or more electrodes are associated with a surface of the balloon, and may be disposed on an outer surface of the balloon. The electrodes are operably coupled to an energy source configured to produce a bipolar or monopolar electric field between two balloon electrodes and/or between one balloon electrode and another electrode placed in contact with a part of the patient&#39;s body. During use, the disclosed drug-delivery catheter produces an electric potential gradient within adjacent tissue, that, in turn, facilitates iontophoresis delivery of a drug. The disclosed catheter can also include a store of one or more drugs to be delivered to the targeted tissue.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/442,788, filed on Apr. 9, 2012, which claims the benefit of, andpriority to, U.S. Provisional Patent Application No. 61/473,569, filedon Apr. 8, 2011, with the entire contents of each of these applicationsincorporated by reference herein for all purposes.

BACKGROUND 1. Technical Field

The present disclosure is related to renal denervation and endovasculardrug delivery. More particularly, the present disclosure is related toan iontophoretic catheter system and method for denervation of the renalsympathetic nerve and iontophoretic drug delivery.

2. Description of Related Art

Chronic elevated blood pressure, or hypertension, is a significant causeof heart disease and death and afflicts millions worldwide. Generally,one having chronic blood pressure of over 140 mm Hg systolic and 90 mmHg diastolic is classified as suffering from hypertension. It isbelieved that renal sympathetic nerve activity initiates, and sustains,the elevation of blood pressure. The renal nerves are bundled around therenal artery, which is readily accessible via the femoral artery. Renaldenervation has been found to reduce blood pressure.

There exist several disadvantages of conventional methods of renaldenervation for the treatment of hypertension. Conventional methodsinvolve the application of intense heat to several discrete sites of therenal artery, which can be very painful to the patient and increaserecovery times. Additionally, the application of intense heat mayproduce flow limiting stenosis. Another disadvantage has to do with notknowing the exact location of the nerve bundle within the artery wall.Therefore, multiple sites must be treated in order to increase theprobability that the renal nerve function will be attenuated.

Another disadvantage includes the difficulty in maintaining appositionwith the blood vessel wall during treatment. Also, conventional renaldenervation treatment systems and methods require moving the catheterlongitudinally as well as rotating the catheter after the treatment ofeach site to avoid the creation of flow-limiting stenosis. Therefore,systems and methods for renal nerve denervation which overcome thedisadvantages of conventional renal nerve denervation systems andmethods would be a welcome advance.

SUMMARY

According to the present disclosure there is provided an iontophoresisdrug delivery system and method for denervation of the renal sympatheticnerve and iontophoresis drug delivery. The system includes aniontophoresis catheter configured to be placed interventionally within apatient. In some embodiment, the iontophoresis catheter is configured tobe placed in the lumen of the renal artery between the descending aortaand/or the one or more renal artery branches adjacent to the kidney. Thedrug delivery catheter includes a balloon near its distal tip or endthat, when inflated, contacts the vessel wall circumferentially.

One or more electrodes are associated with a surface of the balloon, andin some embodiments, the electrodes are disposed on an outer surface ofthe balloon. The electrodes are operably coupled to an energy source.The energy source is configured to produce a bipolar or monopolarelectric field between two balloon electrodes (e.g., bipolar mode)and/or between one balloon electrode and another electrode placed incontact with a part of the patient's body, such as, without limitation,the skin, a blood vessel, and so forth (e.g., monopolar mode). Theenergy source may include a control system that is configured toregulate and monitor energy delivery and/or monitor a related parameter(tissue impedance, contact temperature, tissue temperature, and thelike). In some embodiments, the energy source provides constant-currentdirect current (DC) energy.

The electric field may be continuous or pulsed direct current. Duringuse, the disclosed catheter produces an electric potential gradientwithin adjacent tissue (e.g., blood vessel wall, nerves, and surroundingtissues), that, in turn, facilitates iontophoresis delivery of a drug.

The disclosed catheter can also include a store of one or more drugs tobe delivered to the targeted tissue. In embodiments according to thepresent disclosure, the drugs can be provided as a coating on the outersurface of the balloon. In some embodiments according to the presentdisclosure, the balloon is perforated (e.g., a weeping balloon) suchthat administration of the drug to the balloon lumen causes its transferto the outer surface of the balloon adjacent to the electrode(s).

In some embodiments according to the present disclosure, the drugs areprovided within wells associated with the outer surface of the balloon.The wells are covered with a covering layer that is disrupted when theballoon is inflated, thereby releasing the drug inside the well into thevicinity of the electrode(s). Other embodiments for providing one ormore drugs to the outer surface of the balloon are envisioned within theteachings of the present disclosure. Therefore, the methods describedherein are provided as example methods and are not to be construed aslimiting.

According to an aspect of the present disclosure, there is provided aniontophoresis drug delivery system. The system includes an energysource; a catheter; a balloon disposed at a distal end of the catheter;at least one electrode disposed on a surface of the balloon and operablycoupled to the energy source; and a drug supply operatively associatedwith the balloon. The drug supply is configured to selectively release adrug. The drug supply includes at least one drug. The at least one drugis selected from the group consisting of guanethidine, epinephrine,dimethyl sulfoxide (DMSO), and combinations thereof. The energy sourceis configured to deliver direct current to the at least one electrode.

In some embodiments, an outer surface of the balloon includes at leastone well for storing the drug supply. The at least one well includes acovering layer configured for being disrupted.

In some embodiments, the balloon includes a plurality of perforations influid communication with an interior of the balloon.

In some embodiments, the drug supply is a coating provided on an outersurface of the balloon.

According to another aspect of the present disclosure, there is providedan iontophoresis drug delivery system. The system includes an energysource; a catheter; an expandable member disposed at a distal end of thecatheter; at least one electrode disposed on the expandable member andoperably coupled to the energy source; and a drug supply operativelyassociated with the expandable member. The drug supply is configured toselectively release the drug. The drug supply includes at least onedrug. The at least one drug is selected from the group consisting ofguanethidine, epinephrine, dimethyl sulfoxide (DMSO), and combinationsthereof. The energy source is configured to deliver direct current tothe at least one electrode.

The expandable member is selected from the group consisting of a balloonand a frame. An outer surface of the balloon includes at least one wellfor storing the drug supply. The at least one well includes a coveringlayer configured for being disrupted. The balloon includes a pluralityof perforations in fluid communication with an interior of the balloon.The drug supply is a coating provided on an outer surface of theballoon.

According to still another aspect of the present disclosure, there isprovided an iontophoresis drug delivery catheter. The catheter includesa balloon disposed at a distal end of the catheter; at least oneelectrode disposed on a surface of the balloon and operably coupled toan energy source; and a drug supply operatively associated with theballoon. The drug supply is configured to selectively release the drug.The drug supply includes at least one drug. The at least one drug isselected from the group consisting of guanethidine, epinephrine,dimethyl sulfoxide (DMSO), and combinations thereof.

An outer surface of the balloon includes at least one well for storingthe drug supply. The at least one well includes a covering layerconfigured for being disrupted. The balloon includes a plurality ofperforations in fluid communication with an interior of the balloon. Thedrug supply is a coating provided on an outer surface of the balloon.

According to yet another aspect of the present disclosure, there isprovided a method for the treatment of renal hypertension. The methodincludes placing a drug-delivery catheter in to the lumen of the renalartery; producing an electric potential between the catheter and thenerves adjacent to the renal artery wall; and administering a drug tothe nerves via the electric potential to attenuate the activity of saidnerves.

According to another aspect of the present disclosure, there is provideda method to determine if a hypertensive patient may benefit from a renaldenervation procedure. The method includes measuring blood pressure ofthe hypertensive patient; administering guanethidine to the hypertensivepatient; determining whether the blood pressure of the hypertensivepatient changed subsequent to guanethidine administration; comparing achange in blood pressure to a predetermined value; and performing arenal denervation procedure on the hypertensive patient if the change inblood pressure exceeds the predetermined value.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other advantages will become more apparent from the followingdetailed description of the various embodiments of the presentdisclosure with reference to the drawings wherein:

FIG. 1 is a block diagram of an iontophoresis catheter system fordenervation of the renal nerve having an iontophoresis catheteraccording to an embodiment of the present disclosure wherein thecatheter is fitted with a drug coated balloon having one or moreelectrodes;

FIG. 2 is an enlarged view of the distal end of an iontophoresiscatheter of the iontophoresis catheter system in accordance with anembodiment of the present disclosure;

FIG. 3 is a cross-sectional view of the distal end of the iontophoresiscatheter shown in FIG. 2;

FIG. 4 is an enlarged view of the distal end of an iontophoresiscatheter in accordance with another embodiment of the presentdisclosure; and

FIG. 5 is an enlarged view of the distal end of iontophoresis catheterin accordance with yet another embodiment of the present disclosure.

DETAILED DESCRIPTION

Particular embodiments of the present disclosure are describedhereinbelow with the accompanying notes and drawings; however, it is tobe understood that the disclosed embodiments are merely examples of thedisclosure, which may be embodied in various forms. The terminology usedherein is for the purpose of describing particular embodiments only, andis not intended to be limiting Well-known and/or repetitive functionsand constructions are not described in detail to avoid obscuring thepresent disclosure in unnecessary or redundant detail. Therefore,specific structural and functional details disclosed herein are not tobe interpreted as limiting, but merely as a basis for the claims and asa representative basis for teaching one skilled in the art to variouslyemploy the present disclosure in virtually any appropriately detailedstructure.

As used herein, the term “proximal,” as is traditional, shall refer tothe end of the instrument that is closer to the user, while the term“distal” shall refer to the end that is farther from the user. As usedherein, terms referencing orientation, e.g., “top”, “bottom”, “up”,“down”, “left”, “right”, “o'clock”, and the like are used forillustrative purposes with reference to the figures and correspondingaxes and features shown therein. It is to be understood that embodimentsin accordance with the present disclosure may be practiced in anyorientation without limitation. As used herein, the term “iontophoresis”refers to a drug delivery method in which an electrical current is usedto stimulate drug-carrying ions to pass through intact tissue, such as avessel wall. Like reference members may represent elements which mayperform the same, similar, or equivalent functions.

In embodiments in accordance with the present disclosure, iontophoresisdrug delivery systems and methods are provided. Each drug deliverysystem includes an iontophoresis catheter which may be introduced into abody lumen to deliver a drug, medicament, or other therapeutic substanceto targeted tissue via iontophoresis. In one non-limiting example, thedisclosed catheter may be introduced into the femoral artery, advancedinto the renal artery, and positioned adjacent to the renal nervebundle. Advantageously, an iontophoresis catheter in accordance with thepresent disclosure may enable the attenuation of renal sympathetic nervefunction for the treatment of hypertension by targeted delivery ofguanethidine to the renal nerve bundle. Other applications and otherdrugs are also envisioned.

With reference to FIGS. 1, 2 and 3, there is shown an example embodimentof a iontophoresis drug delivery system for denervation of the renalnerve having an iontophoresis catheter fitted with a drug coated balloonin accordance with the present disclosure. The iontophoresis drugdelivery system is designated generally by reference numeral 100. Thesystem 100 includes the iontophoresis catheter 110 that is configured tobe placed in the lumen of the renal artery between the descending aorta,and/or the one or more of the renal artery branches adjacent to thekidney.

In the embodiment shown by FIG. 1, the catheter 110 includes anexpandable member or balloon 112 at or near its distal end 114 that,when inflated, circumferentially contacts the vessel wall 116, such asthe wall of the renal artery 117 in proximity to the renal nerve 119.One or more electrodes 118 are associated with a surface of the balloon112. In the present embodiment, the electrodes 118 are disposed on anouter surface 120 of the balloon 112. The electrodes 118 are operablycoupled to an energy source 122 via at least one wire 123. The energysource 122 is configured to produce a bipolar or monopolar electricfield between two balloon electrodes 118 (e.g., bipolar mode) and/orbetween one balloon electrode 118 and another balloon electrode 118placed in contact with a part of the patient's body, such as withoutlimitation, the skin, a blood vessel, etc. (e.g., monopolar mode).

The energy source 122 may include a control system that is configured toregulate and monitor energy delivery and/or monitor a related parameter(tissue impedance, contact temperature, tissue temperature, and soforth). In some embodiments, the energy source 122 providesconstant-current DC energy. A return electrode 124 may be included asshown in FIG. 1.

The electric field generated by the system 100 and illustrated by thebroken lines in FIG. 1 may be continuous or pulsed direct current. Theelectrodes 118 may be positioned in any pattern on the outer surface 120of the balloon 112 to provide particular configurations of the electricfield. The electrodes 118 may be positioned in a equally spaced patternas shown by FIGS. 2 and 3, and/or the electrodes 118 can be positionedin random locations on the outer surface 120 of the balloon 112.

The electrodes 118 may be arranged in a manner such that the majority ofthe electric field generated penetrates the renal nerve 119 for optimumdenervation of the renal nerve 119. The electrodes 118 can also bearranged as shown in FIG. 1, such that a tail end of the electric fieldgenerated penetrates the renal nerve 119. As such, according to thepresent disclosure the electrodes 118 can be positioned on the outersurface 120 of the balloon 112 in accordance with the amount of electricfield desired to penetrate the renal nerve 119.

The balloon 112 or distal end 114 of the catheter 110 may also be movedalong the interior of the vessel, such as the renal artery 117, bypushing and pulling the catheter shaft 126. The balloon 112 can be movedalong the interior of the vessel prior to activation of the electrodes118 or during activation of the electrodes 118. The balloon 112 may alsobe moved along the interior of the vessel while it is fully inflated,partially inflated or deflated.

The balloon 112 and/or catheter, such as the catheter shaft 126, caninclude one or more lumens to allow blood to flow from one side of theballoon 112 to the other in order to maintain kidney perfusion duringdenervation of the renal nerve and/or iontophoresis drug delivery. Theone or more lumens, such as lumen 128 shown in FIG. 3, allow the balloon112 to be kept inflated for as long as needed to complete thedenervation procedure, or any other desired procedure. Additionally, thedepth of drug penetration in iontophoresis drug delivery is dependent inpart upon the duration of the applied current.

During use, the disclosed catheter 110 produces an electric potentialgradient within adjacent tissue (e.g., blood vessel wall, nerves, andsurrounding tissues), that, in turn, facilitates iontophoresis deliveryof a drug.

The disclosed iontophoresis drug delivery systems also include a storeof one or more drugs to be delivered to the targeted tissue. Preferably,at least one drug is in an ionic form. For example, and withoutlimitation, guanethidine is a drug known to attenuate the function ofsympathetic nerves by inhibiting the release of norepinephrine (alsoknown as noradrenaline). Guanethidine may be formulated in an ionic formwith a +2 charge. Additionally or alternatively, other drugs may beutilized. For example, and without limitation, a drug may be combinedwith one or more secondary drugs to improve the speed of drug uptake(e.g. penetration or permeation enhancers such as dimethyl sulfoxide(DMSO)) or to prolong the local drug effect (e.g., vasovasorumconstrictors such as epinephrine).

In some embodiments, the catheter 110 includes a supply of a drug (e.g.,prior to drug delivery) and may be configured to facilitate the releasethereof for iontophoresis delivery into a body lumen and/or surroundingtissue. In some embodiments, additionally or alternatively to otherembodiments, the drug may be incorporated into a coating 130 (FIG. 1)surrounding the outer surface 120 of the balloon 112.

Additionally or alternatively to other embodiments, a balloon 140 of theiontophoresis drug delivery system 100 can be perforated (e.g., aweeping balloon), as shown by FIG. 4, such that administration of thedrug to a balloon lumen 142 from a drug supply via, for example, thecatheter shaft 126, causes a transfer of the drug from the inner volumeof the balloon 140 to the outer surface 144 at or adjacent to theelectrode(s) 146 via a plurality of perforations 149. The drug supplymay be external or outside the patient.

In the embodiment shown by FIG. 4, the catheter shaft 126 can be sizedto have approximately the same diameter as the inner surface of theballoon 140. The inner surface of the balloon 140 includes at least oneopening in fluid communication with an inner lumen 141 of the shaft 126.The drug is delivered under pressure through the shaft 126 to theballoon 140 via the at least one opening (not explicitly shown). Thedrug is then forced out of the plurality of perforations 149 to theouter surface of the balloon 140. The drug can also be delivered to theballoon 140 through a lumen other than the catheter shaft 126.

In some embodiments, additionally or alternatively to the otherembodiments, with reference to FIG. 5, the drug is stored in one or morewells 148 disposed on the surface of a balloon 150, each of which iscovered by a covering layer 152. When this covering layer 152 isdisrupted, the drug inside the wells 148 is released into the vicinityof the electrode(s) 154. The covering layer 152 may be disrupted bymechanical action (e.g., pressure applied by the balloon pressingagainst the blood vessel wall) or the application of heat (e.g., ametallic covering is melted by resistive heating through the applicationof electrical energy from the electrode(s) 154).

The covering layer 152 is shown in a non-disrupted state for the bottomtwo wells in FIG. 5, while the covering layer 152 for the top two wellshas been disrupted, for illustrative purposes. In operation, allcovering layers 152 are likely to be disrupted at or about the same timeduring operation of the drug delivery system.

When the drug to be delivered is situated adjacent to the electrodes118, 146, 154, an electric field is applied between two or moreelectrodes. The ionic charge of the drug causes the drug molecules tofollow the electric field, thereby entering the tissue at a faster ratethan would occur by, e.g., simple diffusion. Rapid uptake of drug intothe tissue may be enhanced by electroporation, whereby one or morehigh-voltage pulses are applied to open temporary pores in the tissuethat, in turn, facilitate accelerated drug uptake. Additionally oralternatively, the direct current used for iontophoresis may be pulsed,since tissue impedance decreases with the frequency of the appliedcurrent. The delivery of current is primarily direct current, since thedirection of ionic migration is dependent upon the polarity of theapplied electric field. In some embodiments, an iontophoresis catheterin accordance with the present disclosure may advantageously be used toremove undesirable compounds, drugs, and toxins from targeted tissue.

The aforementioned embodiment describes a balloon catheter. Additionalor alternative methods of producing approximately circumferential vesselwall apposition are also envisioned within the scope of the presentdisclosure. For example, and without limitation, in some embodiments theelectrodes 118, 146, 154 may be mounted on an expandable wire frameresembling an umbrella frame. In some embodiments, the electrodes 118,146, 154 may be mounted on a stent-like expandable member or frame.

Also disclosed is a method for the treatment of renal hypertension. Themethod includes placing a drug delivery catheter, such as the catheter110 shown in FIG. 2, into the lumen of the renal artery 117. The methodfurther includes producing an electric potential between the catheterand the nerves adjacent to the renal artery wall. The method furtherincludes administering a drug, such as the drugs mentioned above, to thenerves via the electric potential, thereby attenuating the activity ofthe nerves.

Also disclosed is a method to determine if a hypertensive patient islikely to benefit from a renal denervation procedure. It is based uponthe established properties of guanethidine, which may suppresssympathetic nerve function. The method include the steps of: (1)measuring a patient's blood pressure; (2) administering guanethidine tothe patient, for example, oral tablet, injection, or intravasculardelivery; (3) measuring changes in the patient's blood pressurefollowing guanethidine administration; (4) comparing the change in bloodpressure to a pre-determined value; and (5) performing a renaldenervation procedure if the change in blood pressure exceeds thepredetermined value.

The drug delivery systems and catheters in accordance with the presentdisclosure have at least the following advantages: (1) there is no heatproduced and therefore the patient experiences no pain; (2) they do notproduce flow-limiting stenosis; (3) the treatment is circumferential,and therefore only one application is needed to guarantee treatment ofthe renal nerve; and (4) the systems and catheters maintain appositionwith the vessel wall during treatment.

The described embodiments of the present disclosure are intended to beillustrative rather than restrictive, and are not intended to representevery embodiment of the present disclosure. Further variations of theabove-disclosed embodiments and other features and functions, oralternatives thereof, may be made or desirably combined into many otherdifferent systems or applications without departing from the spirit orscope of the disclosure as set forth herein and/or in the followingclaims both literally and in equivalents recognized in law.

1-30. (canceled)
 31. An iontophoresis drug delivery system for treatmentof a human patient, the drug delivery system comprising: a cathetershaped and sized for intravascular delivery to a renal blood vessel ofthe patient; an expandable member at a distal region of the catheter;one or more electrodes disposed on the expandable member, wherein theone or more electrodes are configured to be coupled to an energy sourceexternal to the patient; and a drug supply operatively associated withthe balloon and configured to selectively release a drug, wherein thedrug is selected from a group including guanethidine, epinephrine,dimethyl sulfoxide (DMSO), and combinations thereof.
 32. Theiontophoresis drug delivery system of claim 31 wherein the catheter isshaped and sized for intravascular delivery within a lumen of a renalartery of the patient between the descending aorta and one or more renalartery branches adjacent to a kidney of the patient.
 33. Theiontophoresis drug delivery system of claim 31 wherein the expandablemember comprises a frame.
 34. The iontophoresis drug delivery system ofclaim 31 wherein the expandable member comprises a balloon.
 35. Theiontophoresis drug delivery system of claim 34 wherein an outer surfaceof the balloon includes a plurality of wells for storing the drugsupply.
 36. The iontophoresis drug delivery system of claim 35, furthercomprising a covering layer over the wells, and wherein the coveringlayer is configured to be disrupted as the balloon transforms between alow-profile delivery configuration and an expanded treatmentconfiguration.
 37. The iontophoresis drug delivery system of claim 34wherein the drug supply comprises a coating on an outer surface of theballoon.
 38. The iontophoresis drug delivery system of claim 34 whereinthe balloon comprises one or more lumens to allow blood to flowtherethrough.
 39. The iontophoresis drug delivery system of claim 34wherein, when inflated, the balloon is sized and shaped tocircumferentially engage an inner vessel wall of the renal blood vessel.40. The iontophoresis drug delivery system of claim 34 wherein theballoon comprises a weeping balloon a plurality of perforationspositioned to deliver the drug therethrough.
 41. The iontophoresis drugdelivery system of claim 31 wherein the drug is in ionic form.
 42. Theiontophoresis drug delivery system of claim 31 wherein the one or moreelectrodes disposed on the expandable member comprises two electrodesadapted for delivery of a bipolar electric field to target tissue tofacilitate delivery of the drug via iontophoresis.
 43. The iontophoresisdrug delivery system of claim 31 wherein the one or more electrodes areadapted for delivery of a monopolar electric field to target tissue tofacilitate delivery of the drug via iontophoresis.